An epigenetic intervention for neurodegenerative diseases

Alzheimer’s disease (AD) and other neurodegenerative disorders are characterized by altered patterns of neuronal gene expression and cognitive decline. Epigenetic modifications such as histone acetylation are dysregulated in AD and other aging-related neurodegenerative diseases, and the resulting epigenetic alterations may contribute to disease pathology. Small molecule inhibitors of histone-deacetylases (HDACs) represent a class of drugs that act on the epigenome and have potential to provide therapeutic efficacy in neurodegenerative diseases. Eva Benito and colleagues at the German Center for Neurodegenerative Diseases evaluated the effects of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on memory loss and neuronal gene expression patterns in murine models of aging and neurodegeneration. Compared to younger animals, aged mice had impaired spatial memory and lower levels of histone acetylation (at H4K12) among hippocampal neurons. Chronic oral administration of SAHA in aged mice improved spatial memory and increased H4K12 acetylation levels in hippocampal neurons but not in non-neuronal cells. Moreover, SAHA reversed aging-associated changes in RNA splicing and gene expression. Similarly, in a mouse model of AD, chronic oral administration of SAHA improved spatial memory and normalized gene expression patterns in hippocampal neurons towards those observed in healthy controls. Taken together, these findings suggest that SAHA should be further explored for the treatment of neurodegenerative disorders. The accompanying images show the levels of amyloid plaque burden (stained green with thioflavin-S stain, counterstained with DAPI, blue) in the hippocampi of WT (left), AD model mice (center) and AD mice following chronic oral SAHA treatment (right). Note that while SAHA treatment improves cognitive function, it has no effect on hippocampal amyloid load in AD model mice.

Abstract

Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer’s disease (AD). Effective therapies for these diseases are lacking. Here, we evaluated mouse models of age-associated memory impairment and amyloid deposition to study transcriptome and cell type–specific epigenome plasticity in the brain and peripheral organs. We determined that aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region as the result of epigenetic-dependent alterations in gene expression. In both amyloid and aging models, inflammation was associated with increased gene expression linked to a subset of transcription factors, while plasticity gene deregulation was differentially mediated. Amyloid pathology impaired histone acetylation and decreased expression of plasticity genes, while aging altered H4K12 acetylation–linked differential splicing at the intron-exon junction in neurons, but not nonneuronal cells. Furthermore, oral administration of the clinically approved histone deacetylase inhibitor vorinostat not only restored spatial memory, but also exerted antiinflammatory action and reinstated epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This study provides a systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and suggests that histone deacetylase inhibitors should be further explored as a cost-effective therapeutic strategy against age-associated cognitive decline.